Microfluidics deals with the behavior, precise control and manipulation of fluids that are geometrically constrained to a small, typically sub-millimeter scale. Typically, micro means one of the following features: small volumes (mL, μL, nL, pL, fL), small size, low energy consumption, and effects of the micro domain. Typically fluids are moved, mixed, separated or otherwise processed. Numerous applications employ passive fluid control techniques like capillary forces. In some applications external actuation means are additionally used for a directed transport of the media. Examples are rotary drives applying centrifugal forces for the fluid transport on the passive chips. Active micro-fluidics refers to the defined manipulation of the working fluid by active (micro) components as micro pumps or micro valves. Micro pumps supply fluids in a continuous manner or are used for dosing. Micro valves determine the flow direction or the mode of movement of pumped liquids. Often processes which are normally carried out in a lab are miniaturized on a single chip in order to enhance efficiency and mobility as well as reducing sample and reagent volumes. It is a multidisciplinary field intersecting engineering, physics, chemistry, microtechnology and biotechnology, with practical applications to the design of systems in which such small volumes of fluids will be used. Micro-fluidics emerged in the beginning of the 1980's and is used in the development of inkjet print-heads, DNA chips, lab-on-a-chip technology, micro-propulsion, and micro-thermal technologies. Advances in micro-fluidics technology are revolutionizing molecular biology procedures for enzymatic analysis (e.g., glucose and lactate assays), DNA analysis (e.g., polymerase chain reaction and high-throughput sequencing), and proteomics. The basic idea of micro-fluidic biochips is to integrate assay operations such as detection, as well as sample pre-treatment and sample preparation on one chip. An emerging application area for biochips is clinical pathology, especially the immediate point-of-care diagnosis of diseases. In addition, microfluidics-based devices, capable of continuous sampling and real-time testing of air/water samples for biochemical toxins and other dangerous pathogens are desired. Microfluidic technology is creating powerful tools for cell biologists to control the complete cellular environment, leading to new questions and new discoveries. Many diverse advantages of this technology for microbiology include: microenvironmental control ranging from mechanical environment to chemical environment, precise spatiotemporal concentration gradients, mechanical deformation, force measurements of adherent cells, confining cell, exerting a controlled force, fast and precise temperature control, electric field integration, cell culture, plant on a chip and plant tissue culture, and cells-on-a-chip, and body-on-chip, and tissue-on-a-chip.
A goal of modern biology is to understand the molecular mechanisms underlying cellular function. Recent developments combining microfabrication technology with cell culture techniques have produced many novel devices, providing an unprecedented ability to control the cellular environment. This emerging “cells-on-a-chip” in vitro technology has demonstrated great potential for offering faster, cheaper and more accurate prediction of a drug's in vivo pharmacokinetics and pharmacodynamics. As an example, rapid hepatocyte profiling has been demonstrated by several groups. As hepatoxicity is one of the primary causes of late drug withdrawal, having a more pertinent model for liver function would enable an increasingly accurate prediction of human response to drugs. In addition to the liver, cultured cells in microdevices have also been shown to mimic kidney function, lung function, the gastrointestinal tract, the vascular network, and tumor angiogensis. Others have further extended this technology by creating devices that can reproduce multi-organ interactions. A single device is fabricated with multiple compartmentalized microenvironments. Each chamber has a different kind of cell cultured, representing an organ, and the chambers are connected with fluidic conduits. This technology has been coined “human-on-a-chip” or “body-on-a-chip”.
In conventional assays, cells are cultured in a two-dimensional monolayer, immersed in excess medium. In contrast, cells in native tissue are surrounded by extracellular matrix and other supporting cells. This results in drastically different cell microenvironments between cell-based assays and in vivo tissue. This difference results in cell-based assays inadequately modeling the nutrient transport, shear stress, and both chemical and mechanical signaling processes of cells. The proof that improved models are needed is provided by the significant number of drugs that fail late in clinical trials. Consequently, the promising technology of merging cell culture with microfluidics is an exciting alternative because it offers unique advantages over conventional cell-based assays. Microfabrication allows for devices with precisely tailored geometries and flow patterns, resulting in controllable, reproducible and more in vivo-like microenvironments as researchers are able to control the transport of growth factors, reagents and oxygen inside the system. Cells cultivated in microdevices adhere to the walls or support, allowing the perfusion of medium inside the cell culture area. This both improves metabolic waste removal and continually renews nutrient supply, creating a more physiological-like situation. Furthermore, laminar flow in microfluidic systems enables the controlled application of shear stress. Microfluidic devices also allow for the generation of concentration gradients. A gradient can be produced by convergence of flow streams, where sequential segregation and re-addition of the streams produces a smooth gradient across a fluidic channel. This is an important advantage for the microfluidic approach because gradients play a role in a wide range of biological processes including development, inflammation, wound healing, and cancer metastasis. Finally, microfluidic approaches allow for three-dimensional cell culture to mimic the native tissue architecture. These advantages result in microfluidics offering improved correlation to in vivo results, as compared to classic cell culture.
In micro-fluidics, there is particular interest in channel diameters in the range of 10's of nanometers to 10's of millimeters. Since the flow rate of fluid in these systems can range from nanoliters per minute to 100's of microliters per minute, there is a need for precision flow control at low flow rates. The precise control of flow rates may be essential to the micro-device function. Uncontrolled variations in the flow rate and the fluid composition may produce a number of deleterious effects that compromise the utility and function of the device. Also, temporal variations in flow rate, such as pulsations, can produce variations in detector signal, reactions, and damage to materials or biological components in the device. The importance of flow control is even more critical for mixing of streams or creating gradients during the course of the experiment. Conventional pumping systems commonly used in microfluidics generally employ positive displacement methods, where the rate of mechanical displacement of a pump element, e.g., a lead-screw driven piston, peristaltic pump rollers, and syringe plunger movement, provides a proportional rate of liquid flow. This method scales down poorly to low flow rates and is unable to control fluid flow with sufficient accuracy. The origin of the low flow rate inaccuracies include: machining tolerances, bearings, quality, syringe inner diameter tolerances, seal component stiction, mechanical back lash, system back pressure on the delivery components, stepping motor noise, temperature changes, tubing fatigue, system backlash, check valve leakage, pump seal leakage, flexing and creep of mechanical seals, thermal expansion of components and compression of the working fluid. Many of these issues can produce errors in flow rate larger than the flow rates desired in micro-device experiments. Some systems rely on adding an air bubble (syringe), adding system back pressure, pulse dampeners and/or fluid volumes to dampen fluctuations when generating flow. These volumes produce relatively high hydraulic capacitance in the system. This capacitance, in conjunction with the high hydraulic resistance leads to slow time response. Many approaches have the disadvantage of running at a fixed rate and all of the above parameters result in a slow response because of system back pressure decreases (in conduction with the above parameters) catching up to the flow rate or displacement setting. Accordingly, there is a need in the art for a precision flow control system that is capable of delivering fluid at low flow rates in the range of about 1 nanoliter/minute to about 1 Liter/minute and varying the flow rate in a prescribed manner that is both predictable and reproducible as well as having a quick response for both an increase or decrease in flow rate, thus, allowing for biologically relevant fluidic waveforms in microfluidics.